tbuckley/cabot-search huggingface dataset:
Activated NK cells reprogram MDSCs via NKG2D-NKG2DL and IFN-γ to modulate antitumor T-cell response after cryo-thermal therapy
Authors: Peng Peng, Yue Lou, Shicheng Wang, Junjun Wang, Zelu Zhang, Peishan Du, Jiamin Zheng, Ping Liu, Lisa X Xu
Journal: Journal for ImmunoTherapy of Cancer (2022)

Myeloid-derived suppressor cells (MDSCs) can potently inhibit T-cell activity, promote growth and metastasis of tumor and contribute to resistance to immunotherapy. Targeting MDSCs to alleviate their protumor functions and immunosuppressive activities is intimately associated with cancer immunotherapy. Natural killer (NK) cells can engage in crosstalk with multiple myeloid cells to alter adaptive immune responses, triggering T-cell immunity. However, whether the NK-cell-MDSC interaction can modulate the T-cell immune response requires further study. Cryo-thermal therapy could induce the maturation of MDSCs by creating an acute inflammatory environment to elicit a CD4+ Th1-dominant immune response, but the mechanism regulating this process remains unclear.NK cells were depleted and NKG2D was blocked with monoclonal antibodies in vivo. MDSCs, NK cells and T cells were assessed by flow cytometry and isolated by magnetic-activated cell sorting (MACS). MDSCs and NK cells were cocultured with T cells to determine their immunological function. The transcriptional profiles of MDSCs were measured by qRT-PCR and RNA-sequencing. Isolated NK cells and MDSCs by MACS were cocultured to study the viability and maturation of MDSCs regulated by NK cells. TIMER was used to comprehensively examine the immunological, clinical, and genomic features of tumors.NK-cell activation after cryo-thermal therapy decreased MDSC accumulation and reprogrammed immunosuppressive MDSCs toward a mature phenotype to promote T cell antitumor immunity. Furthermore, we discovered that NK cells could kill MDSCs via the NKG2D-NKG2DL axis and promote MDSC maturation by interferon gamma (IFN-γ) in response to NKG2D. In addition, CD4+ Th1-dominant antitumor immune response was dependent on NKG2D, which promoted the major histocompatibility complex Ⅱ pathway of MDSCs. High activated NK-cell infiltration and NKG2D level in tumors were positively correlated with better clinical outcomes.Cryo-thermal therapy induces effective CD4+ Th1-dominant antitumor immunity by activating NK cells to reprogram MDSCs, providing a promising therapeutic strategy for cancer immunotherapy.
Production and possible reduction of greenhouse gases produced during GI endoscopy activity: a systematic review of available literature
Authors: Abhilash Perisetti, Madhav Desai, Michael J Bourke, Ian Penman, Alessandro Repici, Duvvur Nageshwar Reddy, Hisao Tajiri, Douglas K Rex, Cesare Hassan, Prateek Sharma
Journal: Gut (2022)

Background and aims Greenhouse gases (GHGs) that trap heat in the atmosphere are composed of carbon dioxide (CO 2 ), methane, nitrous oxide and fluorinated gases (synthetic hydrofluorocarbons, perfluorocarbons and nitrogen trifluoride). In the USA, the health sector accounts for 8.5% of total GHG emissions. The primary objective of this systematic review was to critically analyse the carbon emissions data from GI endoscopic activity. Design The GI endoscopy carbon cycle was evaluated at preprocedural, intraprocedural and postprocedural levels. We performed a systematic literature search of articles published on these issues until 30 June 2022 and discussed these available data on endoscopy unit GHG carbon cycle, barriers to reduce GHG emissions and potential solutions. The inclusion criteria were any full-text articles (observational, clinical trials, brief communications, case series and editorials) reporting waste generation from GI endoscopy. Abstracts, news articles and conference proceedings were excluded. Results Our search yielded 393 records in PubMed, 1708 in Embase and 24 in Google Scholar. After application of inclusion and exclusion factors, we focused on 9 fulllength articles in detail, only 3 of them were cross-sectional studies (all from the USA), the others reviews or position statements. Therefore, the quality of the studies could not be assessed due to heterogeneity in definitions and amount of emissions. Conclusions Recognition of carbon emissions generated by GI endoscopy activity is critical. Although multiple limitations exists for quantification of these emission, there is an urgent need for collecting proper data as well as examining novel methods for reduction of these emissions for a sustainable endoscopic practices in the future.
Cardiovascular disease risk in paediatric and young adult non-alcoholic fatty liver disease
Authors: Tracey G Simon, Bjorn Roelstraete, Naim Alkhouri, Hannes Hagström, Johan Sundström, Jonas F Ludvigsson
Journal: Gut (2022)

Objective Longitudinal evidence is lacking regarding the long-term risk of major adverse cardiovascular events (MACE) in children and young adults with non-alcoholic fatty liver disease (NAFLD). Design This nationwide cohort study included all Swedish children and young adults ≤25 years old with histologically confirmed NAFLD and without underlying cardiovascular disease (CVD) at baseline (1966–2016; n=699). NAFLD was defined from prospectively recorded histopathology, and further categorised as simple steatosis or non-alcoholic steatohepatitis (NASH). NAFLD patients were matched to ≤5 population controls without NAFLD or CVD (n=3353). Using Cox proportional hazards modelling, we calculated multivariable-adjusted HRs (aHRs) and 95% CIs for incident MACE (ie, ischaemic heart disease, stroke, congestive heart failure or cardiovascular mortality). In secondary analyses, we also explored rates of incident cardiac arrhythmias. Results Over a median follow-up of 16.6 years, incident MACE was confirmed in 33 NAFLD patients and 52 controls. NAFLD patients had significantly higher rates of MACE than controls (3.1 vs 0.9/1000 person-years (PY); difference=2.1/1000 PY; aHR=2.33, 95% CI=1.43 to 3.78), including higher rates of ischaemic heart disease (difference=1.4/1000 PY; aHR=3.07, 95% CI 1.62 to 5.83) and congestive heart failure (difference=0.5/1000 PY; aHR=3.89, 95% CI=1.20 to 12.64). Rates of incident MACE outcomes appeared to be further augmented with NASH (aHR=5.27, 95% CI=1.96 to 14.19). In secondary analyses, NAFLD patients also had significantly higher rates of cardiac arrythmias (aHR=3.16, 95% CI=1.49 to 6.68). Conclusion Compared with matched population controls, children and young adults with biopsy-proven NAFLD had significantly higher rates of incident MACE, including ischaemic heart disease and congestive heart failure. Research to better characterise cardiovascular risk in children and young adults with NAFLD should be prioritised.
COVID-19 and Other Underlying Causes of Cancer Deaths — United States, January 2018–July 2022
Authors: S. Jane Henley, Nicole F. Dowling, Farida B. Ahmad, Taylor D. Ellington, Manxia Wu, Lisa C. Richardson
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Cancer survivors (persons who have received a diagnosis of cancer, from the time of diagnosis throughout their lifespan)* have increased risk for severe COVID-19 illness and mortality (1). This report describes characteristics of deaths reported to CDC's National Vital Statistics System (NVSS), for which cancer was listed as the underlying or a contributing cause (cancer deaths) during January 1, 2018-July 2, 2022. The underlying causes of death, including cancer and COVID-19, were examined by week, age, sex, race and ethnicity, and cancer type. Among an average of approximately 13,000 weekly cancer deaths, the percentage with cancer as the underlying cause was 90% in 2018 and 2019, 88% in 2020, and 87% in 2021. The percentage of cancer deaths with COVID-19 as the underlying cause differed by time (2.0% overall in 2020 and 2.4% in 2021, ranging from 0.2% to 7.2% by week), with higher percentages during peaks in the COVID-19 pandemic. The percentage of cancer deaths with COVID-19 as the underlying cause also differed by the characteristics examined, with higher percentages observed in 2021 among persons aged ≥65 years (2.4% among persons aged 65-74 years, 2.6% among persons aged 75-84 years, and 2.4% among persons aged ≥85 years); males (2.6%); persons categorized as non-Hispanic American Indian or Alaska Native (AI/AN) (3.4%), Hispanic or Latino (Hispanic) (3.2%), or non-Hispanic Black or African American (Black) (2.5%); and persons with hematologic cancers, including leukemia (7.4%), lymphoma (7.3%), and myeloma (5.8%). This report found differences by age, sex, race and ethnicity, and cancer type in the percentage of cancer deaths with COVID-19 as the underlying cause. These results might guide multicomponent COVID-19 prevention interventions and ongoing, cross-cutting efforts to reduce health disparities and address structural and social determinants of health among cancer survivors, which might help protect those at disproportionate and increased risk for death from COVID-19.
Drug Overdose Deaths Among Persons Aged 10–19 Years — United States, July 2019–December 2021
Authors: Lauren J. Tanz, Amanda T. Dinwiddie, Christine L. Mattson, Julie O’Donnell, Nicole L. Davis
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

U.S. drug overdose deaths increased 30% from 2019 to 2020 and 15% in 2021, resulting in an estimated 108,000 deaths in 2021.* Among persons aged 14-18 years, overdose deaths increased 94% from 2019 to 2020 and 20% from 2020 to 2021 (1), although illicit drug use declined overall among surveyed middle and high school students during 2019-2020 (2). Widespread availability of illicitly manufactured fentanyls (IMFs),† proliferation of counterfeit pills resembling prescription drugs but containing IMFs or other illicit drugs,§ and ease of purchasing pills through social media¶ have increased fatal overdose risk among adolescents (1,3). Using CDC's State Unintentional Drug Overdose Reporting System (SUDORS), this report describes trends and characteristics of overdose deaths during July 2019-December 2021 among persons aged 10-19 years (hereafter referred to as adolescents). From July-December 2019 to July-December 2021, median monthly overdose deaths increased 109%, and deaths involving IMFs increased 182%. Approximately 90% of overdose deaths involved opioids, and 83.9% involved IMFs; however, only 35% of decedents had documented opioid use history. Counterfeit pill evidence was present in 24.5% of overdose deaths, and 40.9% of decedents had evidence of mental health conditions or treatment. To prevent overdose deaths among adolescents, urgent efforts are needed, including preventing substance use initiation, strengthening partnerships between public health and public safety to reduce availability of illicit drugs, expanding efforts focused on resilience and connectedness of adolescents to prevent substance misuse and related harms, increasing education regarding IMFs and counterfeit pills, expanding naloxone training and access, and ensuring access to treatment for substance use and mental health disorders.
Erratum: Transcriptomic Signatures in Sepsis and a Differential Response to Steroids. From the VANISH Randomized Trial
Authors: S Ebastien Bailly, Gerv Es-Pinqui, Fr Ed, Eric Gagnadoux
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

described in randomized controlled trials of CV endpoints in the context of OSA (3,7).The second comment from Donovan and Patel concerns the healthy adherer effect and the interpretation of E-values in our study.The healthy adherer effect arises when patients who adhere to preventive therapy are more likely to engage in other healthy behaviors than their nonadherent counterparts.This phenomenon can result in biased estimates of the effect of adherence on clinical outcomes (8).We completely agree with Donovan and Patel that the healthy adherer effect is particularly relevant to comparisons between patients with OSA who are adherent and those who are nonadherent to PAP therapy.This is why we have made the effort to capture the healthy adherer effect by adjusting for chronic CV active drug adherence as assessed by the Medication Possession Ratio, which is considered a valuable proxy (9).Several measures that are particularly relevant to the assessment of CV outcomes in the context of PAP use, such as alcohol intake, tobacco consumption, and socioprofessional status, were also taken into account.Moreover, we applied the recently described E-value to quantify the potential for unmeasured confounding to negate observed treatment effects (10).However, there is no simple way to control for all biases using healthcare datasets (8).We agree with Donovan and Patel that adherence to chronic CV active drugs does not fully capture the healthy adherence effect and that concern for residual confounding remains.Further studies are needed to fully explore the healthy adherer effects in the context of PAP adherence and CV outcomes in patients with OSA.
In Situ Regulation and Mechanisms of 3D Matrix Stiffness on the Activation and Reversion of Hepatic Stellate Cells
Authors: Guobao Chen, Yaxin Deng, Bin Xia, Yonggang Lv
Journal: Advanced Healthcare Materials (2022)

Abstract Activated hepatic stellate cells (HSCs) is a key event in the progression of liver fibrosis. HSCs transdifferentiate into myofibroblasts and secrete large amounts of extracellular matrix, resulting in increased liver stiffness. It is difficult for platforms constructed in vitro to simulate the structure, composition, and stiffness of the 3D microenvironment of HSCs in vivo. Here, 3D scaffolds with different stiffness are constructed by decellularizing rat livers at different stages of fibrosis. The effects of matrix stiffness on the proliferation, activation, and reversion of HSCs are studied. The results demonstrate these scaffolds have good cytocompatibility. It is also found that the high stiffness can significantly promote the activation of HSCs, and this process is accompanied by the activation of integrin β 1 as well as the nucleation and activation of Yes‐associated protein (YAP). Moreover, the low stiffness of the scaffold can promote the reversion of activated HSCs, which is associated with cell apoptosis and accompanied by the inactivation of integrin β 1 and YAP. These results suggest that YAP may be a potential therapeutic target for the treatment of liver fibrosis and the theoretical feasibility of inducing activated HSCs reversion to the resting state by regulating matrix stiffness of liver.
Calculating variant penetrance from family history of disease and average family size in population-scale data
Authors: Thomas P. Spargo, Sarah Opie-Martin, Harry Bowles, Cathryn M. Lewis, Alfredo Iacoangeli, Ammar Al-Chalabi
Journal: Genome Medicine (2022)

Genetic penetrance is the probability of a phenotype when harbouring a particular pathogenic variant. Accurate penetrance estimates are important across biomedical fields including genetic counselling, disease research, and gene therapy. However, existing approaches for penetrance estimation require, for instance, large family pedigrees or availability of large databases of people affected and not affected by a disease.
Alterations in gut microbiome and metabolomics in chronic hepatitis B infection-associated liver disease and their impact on peripheral immune response
Authors: Yue Shen, Sheng-Di Wu, Yao Chen, Xin-Yue Li, Qin Zhu, Kiyoko Nakayama, Wan-Qin Zhang, Cheng-Zhao Weng, Jun Zhang, Hai-Kun Wang, Jian Wu, Wei Jiang
Journal: Gut Microbes (2022)

Gut dysbiosis has been reported in chronic hepatitis B (CHB) infection, however its role in CHB progression and antiviral treatment remains to be clarified. Herein, the present study aimed to characterize gut microbiota (GM) in patients with chronic hepatitis B virus infection-associated liver diseases (HBV-CLD) by combining microbiome with metabolome analyses and to evaluate their effects on peripheral immunity. Fecal samples from HBV-CLD patients (n = 64) and healthy controls (n = 17) were collected for 16s rRNA sequencing. Fecal metabolomics was measured with untargeted liquid chromatography-mass spectrometry in subgroups of 58 subjects. Lineage changes of peripheral blood mononuclear cells (PBMCs) were determined upon exposure to bacterial extracts (BE) from HBV-CLD patients. Integrated analyses of microbiome with metabolome revealed a remarkable shift of gut microbiota and metabolites in HBV-CLD patients, and disease progression and antiviral treatment were found to be two main contributing factors for the shift. Concordant decreases in Turicibacter with 4-hydroxyretinoic acid were detected to be inversely correlated with serum AST levels through host-microbiota-metabolite interaction analysis in cirrhotic patients. Moreover, depletion of E.hallii group with elevated choline was restored in patients with 5-year antiviral treatment. PBMC exposure to BE from non-cirrhotic patients enhanced expansion of T helper 17 cells; however, BE from cirrhotics attenuated T helper 1 cell count. CHB progression and antiviral treatment are two main factors contributing to the compositional shift in microbiome and metabolome of HBV-CLD patients. Peripheral immunity might be an intermediate link in gut microbe-host interplay underlying CHB pathogenesis.
Hyaluronan driven by epithelial aPKC deficiency remodels the microenvironment and creates a vulnerability in mesenchymal colorectal cancer
Authors: Anxo Martinez-Ordoñez, Angeles Duran, Marc Ruiz-Martinez, Tania Cid-Diaz, Xiao Zhang, Qixiu Han, Hiroto Kinoshita, Yu Muta, Juan F. Linares, Hiroaki Kasashima, Yuki Nakanishi, Mohamed Omar, Sadaaki Nishimura, Leandro Avila, Masakazu Yashiro, Kiyoshi Maeda, Tania Pannellini, Alessio Pigazzi, Giorgio Inghirami, Luigi Marchionni, Darren Sigal, Maria T. Diaz-Meco, Jorge Moscat
Journal: Cancer Cell (2022)
Whales in the carbon cycle: can recovery remove carbon dioxide?
Authors: Heidi C Pearson, Matthew S Savoca, Daniel P Costa, Michael W Lomas, Renato Molina, Andrew J Pershing, Craig R Smith, Juan Carlos Villaseñor-Derbez, Stephen R Wing, Joe Roman
Journal: Trends in Ecology & Evolution (2022)

The great whales (baleen and sperm whales), through their massive size and wide distribution, influence ecosystem and carbon dynamics. Whales directly store carbon in their biomass and contribute to carbon export through sinking carcasses. Whale excreta may stimulate phytoplankton growth and capture atmospheric CO
Towards molecular-pathology informed clinical trials in childhood arthritis to achieve precision medicine in juvenile idiopathic arthritis
Authors: Lucy R Wedderburn, Athimalaipet V Ramanan, Adam P Croft, Kimme L Hyrich, Andrew D Dick
Journal: Annals of the Rheumatic Diseases (2022)

In childhood arthritis, collectively known as Juvenile idiopathic arthritis (JIA), the rapid rise of available licensed biological and targeted small molecule treatments in recent years has led to improved outcomes. However, real-world data from multiple countries and registries show that despite a large number of available drugs, many children and young people continue to suffer flares and experience significant periods of time with active disease for many years. More than 50% of young people with JIA require ongoing immune suppression well into adult life, and they may have to try multiple different treatments in that time. There are currently no validated tools with which to select specific treatments, nor biomarkers of response to assist in such choices, therefore, current management uses essentially a trial-and-error approach. A further consequence of recent progress is a reducing pool of available children or young people who are eligible for new trials. In this review we consider how progress towards a molecular based approach to defining treatment targets and informing trial design in JIA, combined with novel approaches to clinical trials, could provide strategies to maximise discovery and progress, in order to move towards precision medicine for children with arthritis.
Malignancy risk with tofacitinib versus TNF inhibitors in rheumatoid arthritis: results from the open-label, randomised controlled ORAL Surveillance trial
Authors: Jeffrey R Curtis, Kunihiro Yamaoka, Yi-Hsing Chen, Deepak L Bhatt, Levent M Gunay, Naonobu Sugiyama, Carol A Connell, Cunshan Wang, Joseph Wu, Sujatha Menon, Ivana Vranic, Juan J Gómez-Reino
Journal: Annals of the Rheumatic Diseases (2022)

To evaluate malignancies and their associations with baseline risk factors and cardiovascular risk scores with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA).In an open-label, randomised controlled trial (ORAL Surveillance; NCT02092467), 4362 patients with RA aged ≥50 years with ≥1 additional cardiovascular risk factor received tofacitinib 5 (N=1455) or 10 mg two times per day (N=1456) or TNFi (N=1451). Incidence rates (IRs; patients with first events/100 patient-years) and HRs were calculated for adjudicated malignancies excluding non-melanoma skin cancer (NMSC), NMSC and subtypes. Post hoc analyses for malignancies excluding NMSC, lung cancer and NMSC included risk factors identified via simple/multivariable Cox models and IRs/HRs categorised by baseline risk factors, history of atherosclerotic cardiovascular disease (HxASCVD) and cardiovascular risk scores.IRs for malignancies excluding NMSC and NMSC were higher with tofacitinib (combined and individual doses) versus TNFi. Risk of lung cancer (most common subtype with tofacitinib) was higher with tofacitinib 10 mg two times per day versus TNFi. In the overall study population, the risk of malignancies excluding NMSC was similar between both tofacitinib doses and TNFi until month 18 and diverged from month 18 onwards (HR (95% CIs) for combined tofacitinib doses: 0.93 (0.53 to 1.62) from baseline to month 18 vs 1.93 (1.22 to 3.06) from month 18 onwards, interaction p=0.0469). Cox analyses identified baseline risk factors across treatment groups for malignancies excluding NMSC, lung cancer and NMSC; interaction analyses generally did not show statistical evidence of interaction between treatment groups and risk factors. HxASCVD or increasing cardiovascular risk scores were associated with higher malignancy IRs across treatments.Risk of malignancies was increased with tofacitinib versus TNFi, and incidence was highest in patients with HxASCVD or increasing cardiovascular risk. This may be due to shared risk factors for cardiovascular risk and cancer.NCT02092467, NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT02147587, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02281552, NCT02187055, NCT02831855, NCT00413699, NCT00661661.
Biomarkers of haemodynamic severity of systemic sclerosis-associated pulmonary arterial hypertension by serum proteome analysis
Authors: Sébastien Sanges, Lisa Rice, Ly Tu, Eleanor Valenzi, Jean-Luc Cracowski, David Montani, Julio C Mantero, Camille Ternynck, Guillemette Marot, Andreea M Bujor, Eric Hachulla, David Launay, Marc Humbert, Christophe Guignabert, Robert Lafyatis
Journal: Annals of the Rheumatic Diseases (2022)

To mine the serum proteome of patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) and to detect biomarkers that may assist in earlier and more effective diagnosis and treatment.
Epidemiology of MRI-detected muscle injury in athletes participating in the Tokyo 2020 Olympic Games
Authors: Hiroki Katagiri, Bruce B Forster, Lars Engebretsen, Jae-Sung An, Takuya Adachi, Yukihisa Saida, Kentaro Onishi, Hideyuki Koga
Journal: British Journal of Sports Medicine (2022)

Muscle injury is one of the most common injuries occurring at the Olympic Games often with devastating consequences. Epidemiological injury surveillance is recognised by the IOC as essential for injury prevention and management. We aimed to describe the incidence, anatomical location and classification of MRI-detected muscle injuries in athletes who participated in the Tokyo 2020 Olympic Games.